Abstract
For an excitable cell to function properly, a precise number of ion channel proteins need to be trafficked to distinct locations on the cell surface membrane, through a network and anchoring activity of cytoskeletal proteins. Not surprisingly, mutations in anchoring proteins have profound effects on membrane excitability. Ca2+- activated K+ channels (K Ca2 or SK) have been shown to play critical roles in shaping the cardiac atrial action potential profile. Here, we demonstrate that filamin A, a cytoskeletal protein, augments the trafficking of SK2 channels in cardiac myocytes. The trafficking of SK2 channel is Ca2+-dependent. Further, the Ca2+ dependence relies on another channel-interacting protein, α-actinin2, revealing a tight, yet intriguing, assembly of cytoskeletal proteins that orchestrate membrane expression of SK2 channels in cardiac myocytes. We assert that changes in SK channel trafficking would significantly alter atrial action potential and consequently atrial excitability. Identification of therapeutic targets to manipulate the subcellular localization of SK channels is likely to be clinically efficacious. The findings here may transcend the area of SK2 channel studies and may have implications not only in cardiac myocytes but in other types of excitable cells.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 9989-9994 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 111 |
| Issue number | 27 |
| DOIs | |
| State | Published - Jul 8 2014 |
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Keywords
- Atrial fibrillation
- Atrial myocytes
- Ion channel trafficking
ASJC Scopus subject areas
- General
Cite this
Functional interaction with filamin A and intracellular Ca2+ enhance the surface membrane expression of a small-conductance Ca 2+-activated K+ (SK2) channel. / Rafizadeh, Sassan; Zhang, Zheng; Woltz, Ryan L.; Kim, Hyo Jeong; Myers, Richard E.; Lu, Ling; Tuteja, Dipika; Singapuri, Anil; Bigdeli, Amir Ali Ziaei; Harchache, Sana Ben; Knowlton, Anne A; Yarov-Yarovoy, Vladimir; Yamoah, Ebenezer N.; Chiamvimonvat, Nipavan.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 27, 08.07.2014, p. 9989-9994.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Functional interaction with filamin A and intracellular Ca2+ enhance the surface membrane expression of a small-conductance Ca 2+-activated K+ (SK2) channel
AU - Rafizadeh, Sassan
AU - Zhang, Zheng
AU - Woltz, Ryan L.
AU - Kim, Hyo Jeong
AU - Myers, Richard E.
AU - Lu, Ling
AU - Tuteja, Dipika
AU - Singapuri, Anil
AU - Bigdeli, Amir Ali Ziaei
AU - Harchache, Sana Ben
AU - Knowlton, Anne A
AU - Yarov-Yarovoy, Vladimir
AU - Yamoah, Ebenezer N.
AU - Chiamvimonvat, Nipavan
PY - 2014/7/8
Y1 - 2014/7/8
N2 - For an excitable cell to function properly, a precise number of ion channel proteins need to be trafficked to distinct locations on the cell surface membrane, through a network and anchoring activity of cytoskeletal proteins. Not surprisingly, mutations in anchoring proteins have profound effects on membrane excitability. Ca2+- activated K+ channels (K Ca2 or SK) have been shown to play critical roles in shaping the cardiac atrial action potential profile. Here, we demonstrate that filamin A, a cytoskeletal protein, augments the trafficking of SK2 channels in cardiac myocytes. The trafficking of SK2 channel is Ca2+-dependent. Further, the Ca2+ dependence relies on another channel-interacting protein, α-actinin2, revealing a tight, yet intriguing, assembly of cytoskeletal proteins that orchestrate membrane expression of SK2 channels in cardiac myocytes. We assert that changes in SK channel trafficking would significantly alter atrial action potential and consequently atrial excitability. Identification of therapeutic targets to manipulate the subcellular localization of SK channels is likely to be clinically efficacious. The findings here may transcend the area of SK2 channel studies and may have implications not only in cardiac myocytes but in other types of excitable cells.
AB - For an excitable cell to function properly, a precise number of ion channel proteins need to be trafficked to distinct locations on the cell surface membrane, through a network and anchoring activity of cytoskeletal proteins. Not surprisingly, mutations in anchoring proteins have profound effects on membrane excitability. Ca2+- activated K+ channels (K Ca2 or SK) have been shown to play critical roles in shaping the cardiac atrial action potential profile. Here, we demonstrate that filamin A, a cytoskeletal protein, augments the trafficking of SK2 channels in cardiac myocytes. The trafficking of SK2 channel is Ca2+-dependent. Further, the Ca2+ dependence relies on another channel-interacting protein, α-actinin2, revealing a tight, yet intriguing, assembly of cytoskeletal proteins that orchestrate membrane expression of SK2 channels in cardiac myocytes. We assert that changes in SK channel trafficking would significantly alter atrial action potential and consequently atrial excitability. Identification of therapeutic targets to manipulate the subcellular localization of SK channels is likely to be clinically efficacious. The findings here may transcend the area of SK2 channel studies and may have implications not only in cardiac myocytes but in other types of excitable cells.
KW - Atrial fibrillation
KW - Atrial myocytes
KW - Ion channel trafficking
UR - http://www.scopus.com/inward/record.url?scp=84904016043&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84904016043&partnerID=8YFLogxK
U2 - 10.1073/pnas.1323541111
DO - 10.1073/pnas.1323541111
M3 - Article
C2 - 24951510
AN - SCOPUS:84904016043
VL - 111
SP - 9989
EP - 9994
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 27
ER -